1. Field of the Invention
The present invention relates to compositions and methods for a high density lipoprotein (HDL) holoparticle uptake receptor for the identification and development of substances (compounds/drugs/therapeutic agents) which modulate the activity and/or expression of the receptor, thereby modulating the uptake of HDL by cells expressing the receptor on the cell surface.
2. Background Art
Epidemiological studies have demonstrated that plasma levels of HDL cholesterol are inversely related to the incidence of coronary heart disease and plasma levels of HDL-cholesterol are useful for predicting an individual's risk of coronary heart disease (Gordon and Rifkind, 1989; Assman and Schulte, 1992). Similarly, levels of Apo-1, the main protein constituent of HDL, are also inversely correlated with cardiovascular disease risk (Stanpfer et al., 1991). Consistent with these studies, is the evidence that HDL has antiatherogenic properties. For example, HDL is known to inhibit oxidation of LDL and transgenic animals having elevated levels of HDL (due to overexpression of ApoA-1) are resistant to high cholesterol diet-induced atherosclerosis (Rubin et al., 1991). Therefore, understanding factors that influence plasma levels of, HDL such as mechanisms of HDL metabolism is of major importance. Unfortunately, there is a poor understanding of HDL catabolism, particularly receptors responsible for mediating the endocytosis and degradation of HDL.
HDL particles are known to facilitate “reverse cholesterol transport,” the transport of excess cholesterol from extrahepatic tissues to the liver for repackaging into new lipoproteins, bile acid synthesis, or excretion into the bile (Eisenberg, 1984; Tall, 1990). Tissues such as the adrenal glands, ovaries and testes are also known to use HDL-cholesterol for steroid hormone biosynthesis. In addition, HDL is important in maternal-fetal lipid nutrition, providing cholesterol and lipid soluble vitamins to the placenta, yolk sac and embryo (Woollett, 1996). HDL is thought to have multiple modes of interaction with cells. One interaction process involves HDL particle binding to the liver or steroidogenic tissues, accompanied by transfer of the cholesterol ester without internalization of the particle (selective lipid uptake). Another process involves the HDL particle being internalized, the cholesterol esters removed and the particle being secreted (retroendocytosed) undegraded. However, no receptor has been identified that mediates HDL holoparticle uptake leading to lysosomal degradation.
The present invention overcomes previous shortcomings in the art by providing an HDL holoparticle uptake receptor comprising a complex of proteins and screening methods for identifying substances which modulate the activity and/or expression of the receptor.